Peripheral arterial disease (PAD) is a highly prevalent disease affecting over 12 million people in the United States (Golomb et al., Circulation, 2006). As PAD progresses, atherosclerosis and chronic inflammation can result in markedly reduced blood flow to the legs, feet, and hands. Critical limb ischemia (CLI) is the most advanced stage of PAD, and affects more than 500,000 people annually, causing rest pain in the foot, non-healing ulcers, delayed wound healing, limb/digital gangrene, and may eventually lead to amputation.
Conventional treatment for severe arterial occlusive disease includes bypassing or crossing the occlusions using endovascular techniques such as angioplasty, atherectomy, and/or stents. However, many patients with severe, diffuse arterial occlusive disease, as is typically seen in CLI, are either not ideal candidates for an endovascular approach to percutaneous revascularization due to their significant co-morbidities (i.e. renal dysfunction, myocardial dysfunction) or significant functional or nutritional debilitation. Moreover, when arterial occlusions are extensive and severely calcified, which is the typical in CLI patients with femoropopliteal and infrapopliteal occlusive disease, interventional attempts to re-establish vessel patency to improve tissue perfusion are frequency sub-optimal or unsuccessful due to inability to traverse these complex, long arterial occlusions. Given this technical failure to re-establish tissue perfusion, amputation is frequently required as a life saving measure, resulting in long-term disability, a diminished quality of life and substantial expenditures to the health care system.
In recent years, stem cell therapies have been investigated as providing a possible adjunct or alternative for patients who are either “poor option” or “no option” candidates for a percutaneous interventional procedures due to extent of their occlusive disease. Stem cells are pluripotent cells with the ability to self-renew and differentiate. The therapeutic effect of stem cells to improve perfusion to ischemic tissues was first observed when administrating bone marrow cells into a mouse model of hind-limb ischemia. (Asahara et al., Circ. Res., 1999). In 2002, autologous bone marrow mononuclear cells were observed to exhibit therapeutic angiogenesis when being injected to a human patient with ischemic limbs due to PAD. (Tateishi-Yuyama et al., Lancet, 2002). While the cellular mechanism(s) behind the therapeutic effect of stem cells is still under investigation, current studies indicate that stem cells promote neo-vascularization by angiogenesis, vasculogenesis, arteriogenesis, or a combination of the three.
Stem cells are conventionally delivered via systemic infusion (i.e., intravenous or intra-arterial) or local injection near areas of ischemic tissue. These delivery methods have remained in use, and relatively static, for over a decade, and may significantly hamper the effectiveness of stem-cell therapy. Specifically, stem cell viability and retention rates after conventional delivery methods are extremely low, typically less than 10% of the injected number. To compensate for the cell loss, a much higher volume of stem cells is needed to elicit a therapeutic response. (Behfar, et al., Circ Cardiovasc Interv, 2013). However, simply injecting a larger number of stem cells cannot compensate for inefficient delivery modalities. Furthermore, stem cells have relatively large diameters and may occlude vessels, compromising their therapeutic effect and potentially contributing to worsening ischemic symptoms. (Perin et al., J Mol Cell Cardiol, 2008).
The suboptimal performance observed with conventional stem cell delivery modalities has multiple causes. First, stem cells differ from traditional therapeutics in that the cells are fragile and extremely sensitive to their microenvironments. Previously known delivery methods deposit the stem cells directly at the occlusion sites, where—due to ischemia, hypoxia, oxidative stress, or inflammation—the microenvironment may be harsh, and contribute to massive cell apoptosis. (Kurtz, et al., Int J Stem Cells, 2008; Li, et. al. Stem Cells, 2007). Further, the cell injection process may itself contribute to poor cell viability, as injection may cause mechanical disruption to the stem cells, e.g., barotrauma caused by fluid sheer and extreme pressure fluctuations. Moreover, in certain applications, such as delivery of stem cells to long femoropopliteal occlusions, the migration of stem cells to ischemic areas may be impeded by the long, calcified occlusions. Alternatively, such stem cells may be easily washed out of the delivery area or entrapped in organs if taken up by systemic circulation.
In view of the foregoing drawbacks of previously known stem cell delivery methods and apparatus, there exists a need for safe and efficacious administration of biologics, such as stem cells, to occluded vessels and ischemic tissue to promote angiogenesis, especially in patients with severely ischemic tissues. In particular, it would be advantageous to provide methods and apparatus for delivering stem cells to ischemic tissue that overcome previously known methods requiring massive direct injections with low migration or uptake, or delivery of stem cells into open arteries in the vicinity of an ischemic tissue, which results in low viability and wash out.
It therefore would be advantageous to provide methods and apparatus for delivering stem cell therapy to patients with severely ischemic tissues, wherein such methods and apparatus enhance cell viability and retention rates, and promote the overall therapeutic effect of stem cells.
It further would be desirable to provide apparatus and methods dedicated to deliver stem cells and other biologics to occluded vessels of a patient in a safe and efficient manner, such that the stem cells may be delivered to the vicinity of an occluded vessel in a protected manner that enhances cell viability and retention, and reduces the risk of wash-out and entry of such cells into systemic circulation.
It also would be desirable to provide apparatus and methods to deliver stem cells such that the stem cells are delivered into a protected environment with reduced mechanical disruption, thereby promoting stem cell viability.
It further would be desirable to provide apparatus and methods for delivering biologics to promote angiogenesis in ischemic tissue that provides uniform distribution of the biologics along a designated region.
It still further would be desirable to provide apparatus and methods suitable for delivering a metered amount of stem cells to the vicinity of an occluded vessel to promote angiogenesis.